Kinetics and mechanism for oxime formation from 4-dimethylaminobenzaldehyde and 4-trimethylammoniobenzaldehyde iodide

Article abstract of DOI:10.1002/(SICI)1097-4601(1999)31:5<387::AID-KIN8>3.0.CO;2-V

The following lines of evidence establish that oxime formation from 4-dimethylaminobenzaldehyde and 4-trimethylammoniobenzaldehyde iodide occurs with a simple two-step mechanism. The pH-rate profile for the reaction of 4-trimethylammoniobenzaldehyde iodid

Full text of DOI:10.1002/(SICI)1097-4601(1999)31:5<387::AID-KIN8>3.0.CO;2-V

Kinetics and Mechanism
for Oxime Formation from
4-Dimethylamino-
benzaldehyde and
4-Trimethylammonio-
benzaldehyde Iodide
A. MALPICA,* M. CALZADILLA,* T. C. CORDOVA, S. TORRES, G. H. SAULNY
*Escuela de Quimica Facultad de Ciencias, Universidad Central de Venezuela, Caracas, Venezuela
Received 2 September 1997; accepted 17 November 1998
ABSTRACT: The following lines of evidence establish that oxime formation from 4-dimethyl-
aminobenzaldehyde and 4-trimethylammoniobenzaldehyde iodide occurs with a simple two-
step mechanism. The pH-rate profile for the reaction of 4-trimethylammoniobenzaldehyde
iodide exhibits, in order of decreasing pH, a negative deviation at pH near 2.0, corresponding
to a transition from rate-determining step carbinolamine dehydration with acid catalysis to
the uncatalyzed carbinolamine formation. In the case of the reaction of 4-dimethylamino-
benzaldehyde, the pH-profile exhibits, in order of decreasing pH, a positive deviation at pH
near 3.5 and then a negative deviation at pH near 2.0. These deviations have been interpreted
in terms of i) transition of the rate-determining step, and ii) protolytic equilibrium of the
substrate. ᭧ 1999 John Wiley & Sons, Inc. Int J Chem Kinet 31: 387–392, 1999
INTRODUCTION
The formation of the carbinolamine, usually the rate-
determining step under mildly acidic conditions, may
occur via two routes: i) a stepwise pathway involving
addition of the amine to the carbonyl group to form a
zwitterionic intermediate followed by protolytic re-
action, or ii) a pathway in which protonation and
amine addition are in some sense concerted. The step-
wise pathway may have three distinct rate-determining
steps at different values of pH: amine addition, pro-
tonation of the zwitterionic species, or a proton switch
that generates the neutral species directly from the
zwitterionic one. Under more basic conditions, the rate
of carbinolamine dehydration becomes the rate-deter-
mining step. This complex reaction mechanism ac-
counts for five separate regions, as well as for many
structure-reactivity correlations [1,2].
The elegant work of Jencks and Sayer has established
the principal features of the mechanism of addition of
nitrogen nucleophiles to the carbonyl group [1,2].
C"O ϩ N9
N9C9OH
C"N9 ϩ H2O
Scheme I
Correspondence to: A. Malpica
᭧ 1999 John Wiley & Sons, Inc.
CCC 0538-8066/99/050387-06

388
MALPICA ET AL.
In this article, we examine the kinetics and mech-
anisms for addition of amines to novel compounds, to
provide additional information to test and extend the
Jencks-Sayer proposal that have been under study.
These include the addition of several amines to N-
methylpyridinecarboxaldehyde ions [3]; the addition
of hydroxylamine to pyridine-2-, -3-, and 4-carbox-
aldehydes [4]; and to 2-quinolinecarboxaldehyde [5].
In the work described herein, attention is directed to
oxime formation from 4-trimethylammoniobenzalde-
hyde iodide and 4-dimethylaminobenzaldehyde. The
cationic nature of 4-trimethylammoniobenzaldehyde
iodide makes it similar in some ways to the conjugate
acids of 4-dimethylaminobenzaldehyde, pyridine-2-,
-3-, and 4-carboxaldehydes, 2-quinolinecarboxalde-
hyde and to N-methylpyridinecarboxaldehyde ions.
For N-methylpyridinecarboxaldehyde ions, oxime,
semicarbazone, and phenylhydrazone formation oc-
curs with rate-determining acid-catalyzed carbinolam-
ine dehydration under acidic, neutral and basic con-
ditions, therefore the pH-rate profiles do not exhibit
breaks [3]. This behavior is attributed to i) strong de-
stabilization of the substrate, and ii) to the fact that the
possession of the cationic center may not increase the
rate of carbinolamine dehydration: that is, the in-
creased equilibrium constant for formation of carbi-
nolamine may be offset or overridden by the effect of
the cationic center on the rate of expulsion of water.
Such expulsion requires protonation of the leaving wa-
ter molecule, and this requires formation of a dica-
tionic specie. These arguments are reinforced by the
behavior of oxime formation from the conjugate acids
of pyridinecarboxaldehydes [4], 2-quinolinecarboxal-
dehyde [5] and by semicarbazone formation from the
conjugate acid of pyridine-2-carboxaldehyde [6]. Pyr-
idine-3- and 4-carboxaldehydes exhibit rate-limiting
acid-catalyzed dehydration of their protonated carbi-
nolamines (similar to the N-methyl derivatives) but the
protonated carbinolamines from 2-quinolinecarboxal-
dehyde, and pyridine-2-carboxaldehyde prefer to lose
a proton and then convert to the product, avoiding in
this way the dicationic species. These results reflect
the influence of proximity between positive charges.
The choice of the substrates in this study arises
from three reasons: i) to establish a comparison be-
tween the equilibrium constants for formation of car-
binolamine and the acid-catalyzed dehydration rate
constants of 4-formyl-1-methylpyridinium and 4-tri-
methylammoniobenzaldehyde ions, ii) as a conse-
quence of the low pKa value of 4-dimethylaminoben-
zaldehyde (pKa ϭ 1.647 [7]) it could be possible to
evaluate its behavior at low pH and, iii) the under-
standing of the kinetics for nucleophilic addition re-
action of the conjugate acid of 4-dimethylaminoben-
zaldehyde is complicated by the protolytic equilibrium
of the substrate, this fact does not exist in the case of
4-trimethylammoniobenzaldehyde iodide, therefore it
provides a model for the protonated 4-dimethylami-
nobenzaldehyde and simplifies data interpretation.
EXPERIMENTAL
Materials
4-Trimethylammoniobenzaldehyde iodide was pre-
pared by refluxing 4-dimethylaminobenzaldehyde
with methyl iodide. The product was recrystallized to
a constant melting point, 157–158a (Lit., m.p. 156–
157 [8]). 4-dimethylaminobenzaldehyde was obtained
commercially and was purified by recrystallization.
Hydroxylamine hydrochloride was obtained commer-
cially and was recrystallized from ethanol. Solutions
of these reagents were prepared just prior to use to
minimize the possibility of decomposition. Distilled
water was used throughout.
Kinetics Measurements
All rate measurements were carried out spectropho-
tometrically employing a Zeiss PMQ II spectropho-
tometer equipped with thermostated cell holders and
photometer-indicator PI-2. Rate constants were mea-
sured in water, at 30Њ, under pseudo-first-order con-
ditions. Ionic strength was maintained at 0.5 with po-
tassium chloride. pH was maintained constant through
use of buffers. Values of pH were measured with Ra-
diometer pH meters. First-order rate constants (kobs
)
were determined from plots of the difference between
optical density at infinite time and optical density
against time in the usual manner. Oxime formation
from 4-trimethylammoniobenzaldehyde iodide was
followed by observing the appearance of the product
at 260 nm. Oxime formation from 4-dimethylamino-
benzaldehyde was followed by observing the disap-
pearance of the substrate at 350 nm. First-order rate
constants were measured at low concentration of hy-
droxylamine, a condition in which carbinolamines do
not accumulate. Second-order rate constants were ob-
tained from the expression k ϭ kobs/(NH2OH)freebase
.
Equilibrium Constants for Carbinolamine
Formation
Equilibrium constants KЈadd and Kadd, at 30Њ, for for-
mation of the neutral carbinolamines of hydroxyl-
amine, 4-dimethylaminobenzaldehyde, and 4-trime-
thylammoniobenzaldehyde iodide, were determined

KINETICS AND MECHANISM FOR OXIME FORMATION
389
spectrophotometrically in 0.125 M phosphate buffer
from the absorbance changes extrapolated to time zero
at pH 8.1, at 350 and 250 nm, respectively, upon mix-
ing a solution of the aldehydes with known concentra-
tions of hydroxylamine. Five amine concentrations be-
tween 0.97 and 3.14 M and between 2.37 ϫ 10Ϫ3 and
5.98 ϫ 10Ϫ3 M were used with 4-dimethylamino- and
4-trimethylammoniobenzaldehyde, respectively. The
changes in absorbance resulting from complete con-
version of the aldehydes to the carbinolamines, deter-
mined from the ordinate intercepts of a double recip-
rocal plot of ⌬A against amine concentration, were ca.
100% of the initial absorbances of the aldehydes. The
equilibrium constants for carbinolamine formation
were determined from the negative abscissa intercepts
of the previous reciprocal plot. In the case of trime-
thylammoniobenzaldehyde iodide, ionic strength was
maintained at 0.5 with potassium chloride. Kadd for 4-
dimethylaminobenzaldehyde is 0.14 MϪ1 and for 4-tri-
1
methylammoniobenzaldehyde iodide is 78.57 MϪ .
RESULT AND DISCUSSION
Figure 2 Logarithms of second-order rate constants for 4-
trimethylammoniobenzaldehyde iodide (᭿) and 4-dimethyl-
aminobenzaldehyde (᭹) oxime formation plotted as a func-
tion of pH. The rate constants were measured at 30Њ and
ionic strength 0.5. The solid lines are theoretical curves
based on Eq. (2) and the rate constants on Table I.
First-order rate constants for 4-trimethylammonio-
benzaldehyde iodide and 4-dimethylaminobenzalde-
hyde oxime formation were determining as a function
of amine concentration over the pH-range ϳ 0 :
ϳ 7 at 30Њ in aqueous solution, ionic strength 0.5. At
values of pH greater than 5 and sufficiently high amine
concentrations, first-order rate constants were ob-
served to increase less rapidly than the concentration
of the amine and eventually level off and become in-
dependent of this variable. Typical example of this
behavior is provided in Figure 1. This conduct agrees
with that observed previously on several occasions and
strongly suggests that carbinolamines formed from the
addition of the amine to the aldehydes accumulate and
that the acid-catalyzed dehydration of these species is
the rate-determining step [9,10].
In Figure 2, logarithms of second-order rate con-
stants (kobs/(NH2OH)fb) for 4-trimethylammonioben-
zaldehyde iodide and 4-dimethylaminobenzaldehyde
oxime formation are plotted as a function of pH. In
the case of 4-trimethylammoniobenzaldehyde iodide
oxime formation the logarithms of the second-order
rate constants increase linearly with the concentration
of the hydrate proton down to a value of pH near 2.
In the reaction with 4-dimethylaminobenzaldehydethe
pH-range in which this behavior is maintained is
shorter, down to a value of pH near 3.5. Below these
limiting pH values, the logarithms of the second-order
rate constants deviate from linearity with pH. In the
first case the observed negative deviation from the rate
expected on the basis of behavior observed at higher
values of pH represents a transition in rate-determin-
Figure 1 First-order rate constants for 4-trimethylammon-
iobenzaldehyde oxime formation plotted as a function of the
concentration of hydroxylamine free base concentration. The
rate constants were measured at 30Њ and ionic strength 0.5,
pH 7.00.

390
MALPICA ET AL.
ing step from acid-catalyzed carbinolamine dehydra-
tion to uncatalyzed carbinolamine formation, accord-
ing to the Scheme II.
the line obtained at high pH values (slope ϭ Ϫ1) in
Figure 2 is now the value that will be named KЈadd k2Ј .
With the value of KaЈdd experimentally determined, k2Ј
was obtained.
The pH-profile of the reaction exhibits below pH
ϳ 3.5, a positive deviation from the observed linearity
at higher values of pH. This fact now represents a dif-
ferent situation because there is at-hand the aldehyde
and its conjugate acid, and the observed constants rep-
resent the reaction of the mixture.
k2(Hϩ)
kadd
C"O ϩ NH2OH
IϪ
kadd
C"N9OH ϩ H2O
Scheme II
The following scheme represents the whole reac-
tion of the mixture of 4-dimethylaminobenzaldehyde
and its conjugate acid.
The steady-state rate law for the mechanism in Scheme
2 is:
kobs/(NH2OH)fb
kЈ2(Hϩ)
kЈadd
ϭ Kad kadd k2 (Hϩ)/[kadd ϩ (Hϩ) Kadd k2] (1)
S0 ϩ NH2OH
I0
P
kЈ-add
where Kadd ϭ kadd/kϪ
.
add
Kac
Rate constants kadd and k2 correspond to the kinet-
ically significant processes that are the most important
for uncatalyzed carbinolamine formation and acid-cat-
alyzed dehydration in reactions of activated aldehydes
and/or basic amines, and pH-rate profiles with only a
negative break at low pH is a good evidence of that
behavior [2].
At high pH values Eq. (1) is transformed to
kobs/(NH2OH)fb) ϭ Kadd k2 (Hϩ). Under this condition,
the antilogarithm of the ordinal intercept of a plot of
log kobs/(NH2OH)fb versus pH (Fig. 2) represents the
value of Kadd k2 . With the value of Kadd determined, k2
was obtained. The complex dependence shows that the
values of kobs, with the concentration of the nucleo-
phile at pH 7.0 (Fig. 1), is strongly suggestive of car-
binolamine accumulation, requiring that dehydration
of this specie be the rate-determining step. The rate
constant for the uncatalyzed formation of the carbi-
nolamine, kadd, was determined from a plot of kobs ver-
sus (NH2OH)fb at pH 1.60, pH in which the steady-
state rate law (1) allows its estimation.
k2(Hϩ)
kadd
SH ϩ NH2OH
IH
P
и
k-add
Scheme III
Where S0 is the aldehyde, SH is the conjugate acid, I0
and IH are their respective carbinolamines, and Kac
(S0)(Hϩ)/(SH). The steady-state rate law for the mech-
anism in Scheme III is:
ϭ
kobs/(NH2OH)fb ϭ (Hϩ)/[Kac ϩ (Hϩ)]
ϫ {KЈadd kЈ2 kaЈdd Kac/[kЈadd ϩ KaЈdd kЈ2 (Hϩ)]
ϩ (Hϩ)Kadd kadd k2/[kadd ϩ Kadd k2 (Hϩ)] (2)
A value of kЈadd was obtained from (2), on the basis of
the experimental value of kobs/NH2OH)fb at pH 3.0.
Figure 2 also shows the hypothetical behavior of
log kobs/(NH2OH)fb with pH in oxime formation from
the pure aldehyde (dashed line). This conduct was cal-
culated assuming a steady-state rate law for the reac-
tion:
The solid line in Figure 2 for the oxime formation
from 4-trimethylammoniobenzaldehyde iodide is cal-
culated based on the law of Eq. (1). The agreement of
theory with experimental data result is satisfying.
kobs/(NH2OH)fb ϭ
KЈadd kЈ2 kЈadd (Hϩ)/[kaЈdd ϩ KaЈdd kЈ2 (Hϩ)] (3)
Figure 2 also shows the behavior of log kobs
/
A summary of rate and equilibrium constants for ox-
ime formation from 4-dimethylaminobenzaldehyde
and 4-trimethylammoniobenzaldehyde iodide is pro-
vided in Table I.
As it was commented in the introduction of this
study, the stepwise pathway for carbinolamine for-
mation may have two distinct uncatalyzed rate-deter-
mining steps at different values of pH: amine addition
to form a zwitterionic intermediate and a proton switch
which generates the neutral specie from the zwitteri-
onic one, for example, the pH-rate profile for semi-
carbazone formation from 4-nitrobenzaldehyde [2] ex-
(NH2OH)fb with pH of oxime formation from 4-di-
methylaminobenzaldehyde. Note the similitude of val-
ues of kobs/(NH2OH)fb at pH near 0 for both studied
reactions; since the pKa value of 4-dimethylamino-
benzaldehyde is 1.647 [7], this fact is strongly sug-
gestive that 4-trimethylammoniobenzaldehyde iodide
is a good model for the conjugate acid of 4-dimethyl-
aminobenzaldehyde, and the low pKa value assures
that the behavior of the reaction at high pH values (pH
6.5 : ϳ 3.5) represents oxime formation from the al-
dehyde itself; therefore the antilogarithm at pH 0 of

KINETICS AND MECHANISM FOR OXIME FORMATION
391
Table I Summary of Rate and Equilibrium Constants for 4-Dimethylaminobenzaldehyde and 4-Trimethylammonio-
benzaldehyde Iodide Oxime Formation in Aqueous Solutions at 30Њ and Ionic Strength 0.5.
Ϫ1
Ϫ
1
Ϫ1
Ϫ1
Ϫ1
Ϫ2
Ϫ1
Substrate
Kadd (M
)
k2 (M min
)
kadd (M min
)
Kadd k2 (M min )
ϩ
(Me)3N Ϫ
78.57
0.14
1.27 ϫ 106
2.26 ϫ 107
6.75 ϫ 106
1.06 ϫ 104
1 ϫ 108
3.16 ϫ 106
(Me)2 NϪ
hibits a negative deviation with decreasing pH, at pH
ϳ 4. This fact is attributed to a change in rate-deter-
mining step, from rate-limiting step dehydration of the
carbinolamine to formation of the neutral carbinolam-
ine by a proton switch of the zwitterionic intermediate.
In addition to this behavior a second change in rate-
determining step was observed at pH ϳ 0 where un-
catalyzed amine addition becomes rate-limiting. Hy-
droxylamine is considerably more basic than
semicarbazide; this will tend to stabilize the zwitteri-
onic intermediate increasing the rate of the proton
switch relative to the decomposition of this specie to
the reactants. Consequently, it appears most reason-
able to ascribe the observed pH-independent reaction
under acidic-condition for oxime formation from 4-
dimethylaminobenzaldehyde to uncatalyzed attack,
not the proton switch step. This corresponds to a pos-
sibility raised earlier [2].
There are some interesting facts to comment in re-
lation to the values of constants in Table I and their
comparison with the values for the same constants for
pyridine-4-carboxaldehyde and 4-formyl-1-methyl-
pyridinium ion oxime formation (Table II). On the one
hand the smaller value of Kadd k2 of 4-dimethylami-
nobenzaldehyde oxime formation in comparison with
the same value of the trimethylated substrate appears
to be a consequence of the difference between their
equilibrium constants of addition and not of their de-
hydration rate constants. Usually the additional com-
pounds are stabilized, relative to the starting benzal-
dehyde with its electron-withdrawing carbonyl group,
by electron-withdrawing substituents, and in contrast
the rates of acid-catalyzed dehydration are aided by
electron donation to the reaction center. Since the
overall rate of the imine formation at neutral pH de-
pends on both the equilibrium constant for addition
and the rate constant for dehydration, these two sub-
stituent effects cancel each other and the observed
rates show almost no variation with changing substit-
uent; for example, in semicarbazone formation from a
serie of substituted benzaldehydes [11], the equilib-
rium constants for the formation of semicarbazide ad-
dition compounds show a linear correlation with Ham-
mett’s substituent, ␴, with a ␳-value of 1.81. The
acid-catalyzed dehydration rate constants show a ␳-
value of Ϫ1.74, but the observed rates show a ␳-value
of 0.07. Cordes et al. [12], in a study of the dehydra-
tion of the addition intermediate formed from benz-
aldehyde and semicarbazide or phenylhydrazine, dem-
onstrated that the kinetic secondary deuterium isotope
effects are large, and Jencks and coworkers [13,14]
have established that Brønsted ␣ values for general
acid catalyzed carbinolamine decomposition are also
large. These facts agree with the suggestion of a sub-
stantial positive charge on carbinolamine oxygen and
a small amount of C–O cleavage in the transition
state. In this study the dehydration rate constants show
little variation when the substituent changes from 4-
dimethylamino to 4-trimethylammonio, suggesting a
transition state similar to the carbinolamine, with the
bulk of the positive charge concentrated on oxygen
and little on carbon.
On the other hand, a comparison between equilib-
rium constants in Table I and the same constants in
oxime formation from pyridine-4-carboxaldehyde [4]
and its N-methyl derivative [3] (Table 2) indicates that
Table II Rate and Equilibrium Constants for Pyridine-4-Carboxaldehyde and Formyl-1-Methylpyridinium Ion Oxime
Formation.
Ϫ1
Ϫ
1
Ϫ1
Ϫ2
Ϫ1
Substrate
Kadd (M
)
k2 (M min
)
Kadd k2 (M min )
ϩ
a
a
a
4.3 ϫ 104
7 ϫ 103
3 ϫ 108
Me9N
CHO
b
b
469b
3 ϫ 105
1.69 ϫ 108
N
CHO
a: Reference 4.
b: Reference 5.

392
MALPICA ET AL.
pyridinecarboxaldehydes have more affinity for the
amine than 4-dimethylaminobenzaldehyde and its N-
methyl derivative. Note that in respect to 4-formyl-1-
methylpyridinium ion, 4-trimethylammoniobenzalde-
BIBLIOGRAPHY
1. Rosenberg, S.; Silver S. M.; Sayer, J. M.; Jencks, W. P.
J Am Chem Soc 1974, 96, 7986.
2. Sayer, J. M.; Pinsky, B.; Schonbrunn, A.; Washtien, W.
J Am Chem Soc 1974, 96, 7998.
hyde iodide has
a 547-fold reduction in the
equilibrium constant and an increment of 181-fold in
the dehydration rate constant. The reduction can be
explained by the electron-attractive effect of the pos-
itive nitrogen atom in the pyridine ring in relation to
the positive nitrogen atom attached to the aromatic
ring. The ␴-value of the ␳-ammonio group is similar
to that of the p-nitro group, but the sigma value of
azonium substituents are by far the largest known;
therefore this exalted quality should favor the addition
of the nucleophile to the carbonyl group. The greater
distance between the positive charges of the dicationic
specie is responsible for the observed increment. In
relation to the equilibrium constants of 4-dimethylam-
inobenzaldehyde and pyridine-4-carboxaldehyde, the
noted difference (3350-fold reduction) probably is
given by the difference between an electron-releasing
and an electron-withdrawing substituent. Finally, the
small difference observed between their dehydration
constants (ϳ 63) suggest transition states with little
positive charge on carbon.
3. Sojo, P.; Viloria, F.; Malave, L.; Possamai, R.; Calza-
dilla, M.; Baumrucker, J.; Malpica, A.; Moscovici, R.;
do Amaral, L. J Am Chem Soc 1976, 98, 4519.
4. Malpica, A.; Calzadilla, M.; Baumrucker, J.; Jimenez,
J.; Lopez, L.; Escobar, G.; Montes, C. J Org Chem 1994,
59, 3398.
5. Calzadilla M.; Malpica, A.; Diaz, P. M. Int J Chem Ki-
net 1996, 28, 687.
6. Ledezma, J. Trabajo Especial de Grado. Licenciatura en
Qu`ımica Escuela de Qu`ımica, Facultad de Ciencias
U.C.V. Julio 1973.
7. Jencks, W. P.; Regenstein, J. In Handbook of Biochem-
istry, Sober, H. A., Eds.; Chemical Rubber Co.; Cleve-
land, OH, 1968; b-J-66.
8. Wiley, G. R.; Miller, S. I. J Org Chem 1972, 37, 767.
9. Jencks, W. P. Prog Phys Org Chem 1964, 2, 63.
10. Jencks, W. P.; Catalysis in Chemistry and Enzymology;
McGraw-Hill: New York. Chapter 10, p. 463 and ref-
erences therein 1969.
11. Anderson B. M.; Jencks, W. P. J Am Chem Soc 1960,
82, 1773.
12. do Amaral, L.; Bastos, M. P.; Bull, H. G.; Cordes, E.
H. J Am Chem Soc 1973, 82; 7369.
13. Sayer, J. M.; Jencks, W. P. J Am Chem Soc 1969, 91,
6353.
Supported in part by the Consejo de Desarrollo Cient`ıfico y
Human`ıstico Universidad Central de Venezuela
14. Sayer, J. M.; Peskin, M.; Jencks, W. P. J Am Chem Soc
1973, 95, 4277.